Genetic contribution of the leukotriene pathway to coronary artery disease

Jaana Hartiala, Dalin Li, David V. Conti, Susanna Vikman, Yesha Patel, W. H. Wilson Tang, Marie Louise Brennan, John W. Newman, Charles B. Stephensen, Patrice Armstrong, Stanley L. Hazen, Hooman Allayee

Research output: Contribution to journalArticle

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Abstract

We evaluated the genetic contribution of the leukotriene (LT) pathway to risk of coronary artery disease (CAD) in 4,512 Caucasian and African American subjects ascertained through elective cardiac evaluation. Of the three previously associated variants, the shorter "3" and "4" alleles of a promoter repeat polymorphism in ALOX5 increased risk of CAD in African Americans (OR = 1.4, 95% CI 1.0-1.9; p = 0.04), whereas a haplotype of LTA4H (HapK) was associated with CAD in Caucasians (OR = 1.2, 95% CI 1.01-1.4; p = 0.03). In Caucasians, first-stage analysis of 254 haplotype-tagging SNPs in 15 LT pathway genes with follow-up of 19 variants in stage 2 revealed an LTA4H SNP (rs2540477) that increased risk of CAD (OR = 1.2, 95% CI 1.1-1.5; p = 0.003) and a PLA2G4A SNP (rs12746200) that decreased risk of CAD (OR = 0.7, 95% CI 0.6-0.9; p = 0.0007). The PLA2G4A rs12746200 variant also decreased risk of experiencing a major adverse cardiac event (MACE = myocardial infarction, stroke, or death) over 3 years of follow-up (HR = 0.7, 95% CI 0.5-0.9; p = 0.01), consistent with its cardioprotective effect. Functional experiments demonstrated that stimulated monocytes from carriers of LTA4H variants HapK or rs2540477 had 50% (p = 0.002) and 33% (p = 0.03) higher LTB4 production, respectively, compared to non-carriers. These ex vivo results are consistent with LTB4 being the direct product of the reaction catalyzed by LTA4H and its role in promoting monocyte chemotaxis to sites of inflammation, including the artery wall of atherosclerotic lesions. Taken together, this study provides additional evidence that functional genetic variation of the LT pathway can mediate atherogenic processes and the risk of CAD in humans.

Original languageEnglish (US)
Pages (from-to)617-627
Number of pages11
JournalHuman Genetics
Volume129
Issue number6
DOIs
StatePublished - Jun 2011

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Leukotrienes
Coronary Artery Disease
Single Nucleotide Polymorphism
Leukotriene B4
African Americans
Haplotypes
Monocytes
Chemotaxis
Arteries
Stroke
Alleles
Myocardial Infarction
Inflammation
Genes

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Hartiala, J., Li, D., Conti, D. V., Vikman, S., Patel, Y., Wilson Tang, W. H., ... Allayee, H. (2011). Genetic contribution of the leukotriene pathway to coronary artery disease. Human Genetics, 129(6), 617-627. https://doi.org/10.1007/s00439-011-0963-3

Genetic contribution of the leukotriene pathway to coronary artery disease. / Hartiala, Jaana; Li, Dalin; Conti, David V.; Vikman, Susanna; Patel, Yesha; Wilson Tang, W. H.; Brennan, Marie Louise; Newman, John W.; Stephensen, Charles B.; Armstrong, Patrice; Hazen, Stanley L.; Allayee, Hooman.

In: Human Genetics, Vol. 129, No. 6, 06.2011, p. 617-627.

Research output: Contribution to journalArticle

Hartiala, J, Li, D, Conti, DV, Vikman, S, Patel, Y, Wilson Tang, WH, Brennan, ML, Newman, JW, Stephensen, CB, Armstrong, P, Hazen, SL & Allayee, H 2011, 'Genetic contribution of the leukotriene pathway to coronary artery disease', Human Genetics, vol. 129, no. 6, pp. 617-627. https://doi.org/10.1007/s00439-011-0963-3
Hartiala J, Li D, Conti DV, Vikman S, Patel Y, Wilson Tang WH et al. Genetic contribution of the leukotriene pathway to coronary artery disease. Human Genetics. 2011 Jun;129(6):617-627. https://doi.org/10.1007/s00439-011-0963-3
Hartiala, Jaana ; Li, Dalin ; Conti, David V. ; Vikman, Susanna ; Patel, Yesha ; Wilson Tang, W. H. ; Brennan, Marie Louise ; Newman, John W. ; Stephensen, Charles B. ; Armstrong, Patrice ; Hazen, Stanley L. ; Allayee, Hooman. / Genetic contribution of the leukotriene pathway to coronary artery disease. In: Human Genetics. 2011 ; Vol. 129, No. 6. pp. 617-627.
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